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Combinatorial Chemistry & High Throughput Screening


ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Synthesis and Biological Analysis of Anti-addiction Effect and Hepatotoxicity of Tow Baclofen Analogues Complexed with β-Cyclodextrin

Author(s): Assia Keniche*, Ibtissem EL Ouar, Ibtissem Zeghina and Mohammed El Amine Dib

Volume 25, Issue 1, 2022

Published on: 08 December, 2020

Page: [187 - 196] Pages: 10

DOI: 10.2174/1386207323666201209093240

Price: $65


Aim and Objective: The excessive consumption of alcohol and the installation of dependence is, in most cases, facilitated by favorable psychological factors that trigger and maintain the behavior of consumers. Examples more frequently encountered in individuals having difficulty with alcohol are, in particular: one or more anxiety disorders, deficits in the capacities to manage stress and anxiety. The main objective of this work was to study in vivo the anti-addiction effect and hepatotoxicity of tow baclofen analogues complexed with β-Cyclodextrin (βCD) on an alcohol-dependent rat model.

Materials and Methods: The synthesis of two analogues, ABF1 and ABF2, close to baclofen was reported. The structural determination of the two compounds was confirmed by NMR and IR analysis. The complexation of analogues with β-Cyclodextrin (βCD) was performed in water at room temperature (25 °C). The interactions of ABF with β-Cyclodextrin, and the stability constant (Ka) of the inclusion complex formed between them were investigated by using UV-visible spectroscopy. The biological effects of baclofen and the two analogues on alcohol dependence were studied in wistar rats. The anti-addiction effect of the analogues was tested by measuring the alcohol intake and the variation of the animal behaviour. The toxicity of the compounds was also analysed on liver injury markers.

Results: The amino-3-phenylbutanoic acid (ABF1) and 3,4,5-trihydroxy-N-(methyl-2-acetate) benzamide (ABF2) were synthesized. The complexation of both analogues of baclofen (BF) with β-cyclodextrin (βCD) (ABF- βCD) was realized and confirmed by the stability constant of the inclusion complex (Ka) and Job’s method. The evaluation of anti-addiction activity in vivo showed that ABF1-βCD inhibits the consumption of alcohol at doses equivalent to those of baclofen. Both baclofen analogues have shown an anxiolytic effect. Regarding the toxicity of the two compounds, our results showed that ABF1-βCD has less toxic effect than baclofen; it reduces the activity of ALT and AST enzymes. Histologically, ABF1-βCD has no effect on the liver structure and has a protective effect against lesions alcohol-induced liver disease.

Conclusion: Therefore, it can be suggested that ABF1 analogue combined with β-Cyclodextrin can be used as a treatment for alcohol dependence. Further clinical works are needed to confirm its effectiveness.

Keywords: Baclofen, cyclodextrin, inclusion complex, analogues, anti-addiction, hepatotoxicity activities.

Graphical Abstract
Hudgson, P.; Weightman, D. Baclofen in the treatment of spasticity. BMJ, 1971, 4(5778), 15-17.
[] [PMID: 4938243]
Froestl, W.; Mickel, S.J.; von Sprecher, G.; Diel, P.J.; Hall, R.G.; Maier, L.; Strub, D.; Melillo, V.; Baumann, P.A.; Bernasconi, R. Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists. J. Med. Chem., 1995, 38(17), 3313-3331.
[] [PMID: 7650685]
Agabio, R.; Maccioni, P.; Carai, M.A.; Gessa, G.L.; Froestl, W.; Colombo, G. The development of medications for alcohol-use disorders targeting the GABAB receptor system. Recent Patents CNS Drug Discov., 2012, 7(2), 113-128.
[] [PMID: 22574677]
Agabio, R.; Colombo, G. [GABAB receptor as therapeutic target for drug addiction: from baclofen to positive allosteric modulators] Psychiatr. Pol., 2015, 49(2), 215-223.
[] [PMID: 26093587]
Agabio, R.; Colombo, G. GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence. Front. Neurosci., 2014, 8(140), 140.
[] [PMID: 24936171]
Ameisen, O. Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician. Alcohol Alcohol., 2005, 40(2), 147-150.
[] [PMID: 15596425]
Ameisen, O. Le Dernier Verre. Paris: Denoël, English Edition: The end of my addiction; Sarah Crichton Books: New York, NY, 2008.
de Beaurepaire, R. A review of the potential mechanisms of action of baclofen in alcohol use disorder. Front. Psychiatry, 2018, 9(506), 506.
[] [PMID: 30459646]
Attia, M.; Herdeis, C.; Bräuner-Osborne, H. Synthesis and pharmacological characterization of certain baclofen analogues. Dig. J. Nanomater. Biostruct., 2012, 8(1), 139-149.
van Bree, J.B.; Heijligers-Feijen, C.D.; de Boer, A.G.; Danhof, M.; Breimer, D.D. Stereoselective transport of baclofen across the blood-brain barrier in rats as determined by the unit impulse response methodology. Pharm. Res., 1991, 8(2), 259-262.
[] [PMID: 2023878]
Deguchi, Y.; Inabe, K.; Tomiyasu, K.; Nozawa, K.; Yamada, S.; Kimura, R. Study on brain interstitial fluid distribution and blood-brain barrier transport of baclofen in rats by microdialysis. Pharm. Res., 1995, 12(12), 1838-1844.
[] [PMID: 8786954]
Keniche, A.; Keniche, N.; Si Said, M.A.; Malti, I.; Kajima Mulengi, J. Baclofen as anti-craving agent against several addiction. Int. J. Complement Alt. Med, 2017, 9(5), 1-6.
Iacovino, R.; Rapuano, F.; Caso, J.V.; Russo, A.; Lavorgna, M.; Russo, C.; Isidori, M.; Russo, L.; Malgieri, G.; Isernia, C. β-Cyclodextrin inclusion complex to improve physicochemical properties of pipemidic acid: characterization and bioactivity evaluation. Int. J. Mol. Sci., 2013, 14(7), 13022-13041.
[] [PMID: 23799358]
Krzak, A.; Bilewicz, R. Voltammetric/UV-Vis study of temozolomide inclusion complexes with cyclodextrin derivatives. Bioelectrochemistry, 2020, 136(7)107587
[] [PMID: 32645568]
Keniche, A.; Slimani, M.Z.; José Miranda, I.; Jesus Azipura, M.; Kajima Mulengi, J. NMR Investigation of the complexation of (S)-2-isopropyl-1-(o-cyclodextrinβnitrophenyl) sulfonyl) aziridine with β-cyclodextrin. Mediterr. J. Chem., 2014, 2(5), 620-631.
Ding, Y.; Pang, Y.; Vara Prasad, C.V.N.S.; Wang, B.; Wang, B. Formation of inclusion complex of enrofloxacin with 2-hydroxypropyl-β-cyclodextrin. Drug Deliv., 2020, 27(1), 334-343.
[] [PMID: 32090640]
Jacob, S.; Nair, A.B. Cyclodextrin complexes: Perspective from drug delivery and formulation. Drug Dev. Res., 2018, 79(5), 201-217.
[] [PMID: 30188584]
Challa, R.; Ahuja, A.; Ali, J.; Khar, R.K. Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech, 2005, 6(2), E329-E357.
[] [PMID: 16353992]
Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea. J. Am. Chem. Soc., 2005, 127(1), 119-125.
[] [PMID: 15631461]
Benesi, H.A.; Hildebrand, J.H. A spectrophotometric investigation of the interaction of iodine with aromatic hydrocarbons. J. Am. Chem. Soc., 1949, 71, 2703-2707.
Planeta, C.S. Animal models of alcohol and drug dependence. Br. J. Psychiatry, 2013, 35(2), 140-146.
[] [PMID: 23846995]
Brenes Sáenz, J.C.; Villagra, O.R.; Fornaguera Trías, J. Factor analysis of Forced Swimming test, Sucrose Preference test and Open Field test on enriched, social and isolated reared rats. Behav. Brain Res., 2006, 169(1), 57-65.
[] [PMID: 16414129]
Teegarden, S. Behavioral phenotyping in rats and mice. Mater. Methods, 2012, 2, 122.
Li, N.; Zhang, Y.H.; Wu, Y.N.; Xiong, X-L.; Zhang, Y.H. Inclusion complex of trimethoprim with β-cyclodextrin. J. Pharm. Biomed. Anal., 2005, 39(3-4), 824-829.
[] [PMID: 16011886]
Zhanga, M.; Lib, J.; Jiaa, W.; Chaob, J.; Zhang, L. Theoretical and experimental study of the inclusion complexes of ferulic acid with cyclodextrin. Supramol. Chem., 2009, 21(7), 597-602.
Huang, C.Y. Determination of binding stoichiometry by the continuous variation method: the Job plot. Methods Enzymol., 1982, 87, 509-525.
[] [PMID: 7176926]
Ozburn, A.R.; Falcon, E.; Mukherjee, S.; Gillman, A.; Arey, R.; Spencer, S.; McClung, C.A. The role of clock in ethanol-related behaviors. Neuropsychopharmacology, 2013, 38(12), 2393-2400.
[] [PMID: 23722243]
Ron, D.; Barak, S. Molecular mechanisms underlying alcohol-drinking behaviours. Nat. Rev. Neurosci., 2016, 17(9), 576-591.
[] [PMID: 27444358]
Colombo, G.; Addolorato, G.; Agabio, R.; Carai, M.A.M.; Pibiri, F.; Serra, S.; Vacca, G.; Gessa, G.L. Role of GABA(B) receptor in alcohol dependence: reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics. Neurotox. Res., 2004, 6(5), 403-414.
[] [PMID: 15545024]
Prut, L.; Belzung, C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. Eur. J. Pharmacol., 2003, 463(1-3), 3-33.
[] [PMID: 12600700]
Bourin, M.; Hascoët, M. The mouse light/dark box test. Eur. J. Pharmacol., 2003, 463(1-3), 55-65.
[] [PMID: 12600702]
Brancatelli, G.; Furlan, A.; Calandra, A.; Dioguardi Burgio, M. Hepatic sinusoidal dilatation. Abdom. Radiol. (N.Y.), 2018, 43(8), 2011-2022.
[] [PMID: 29392360]
Wolf, E.; Kothari, N.R.; Roberts, J.K.; Sparks, M.A. Baclofen toxicity in kidney disease. Am. J. Kidney Dis., 2018, 71(2), 275-280.
[] [PMID: 28899601]
Bonaventura, M.M.; Catalano, P.N.; Chamson-Reig, A.; Arany, E.; Hill, D.; Bettler, B.; Saravia, F.; Libertun, C.; Lux-Lantos, V.A. GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice. Am. J. Physiol. Endocrinol. Metab., 2008, 294(1), E157-E167.
[] [PMID: 17971510]
Naumenko, A.M.; Shapoval, L.M.; Nyporko, A.Y.; Voiteshenko, M.I.; Tsymbalyuk, A.V.; Sagach, V.F.; Davydovska, T.L. Computer simulation of molecular interaction between baclofen and the GABAB receptor. Neurophysiol., 2017, 49(2-7), 1-7.

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